Sajish Mathew, University of South Carolina
The effects of a drug or chemical compound on the body depend on how its atoms are arranged in space. Some compounds have a dark twin with the same molecular formula but a different 3D structure – and this can have consequences for what they do or don’t do in the body.
Consider the tragic story of thalidomide, a morning sickness drug that caused thousands of birth defects and miscarriages. While one form, or isomer, of thalidomide has a sedative effect, the other is thought to cause abnormal physiological development. Since both versions can convert in the body, it is dangerous to take either form of thalidomide during pregnancy.
My research focused on one such compound found in red grapes and peanuts, resveratrol. Why clinical trials of using resveratrol to treat Alzheimer’s disease have yielded inconsistent results is a scientific mystery. Turns out it may be because two different forms were used – while one may help with cognition and memory, the other may be toxic to the nervous system.
Isomers and amino acids
Many drugs have the same atoms and bonds, but are arranged differently in space. These drugs are called chiral compounds – meaning that they exist as two non-overlapping mirror images. For example, your hands are also non-superimposable mirror images of each other. Although they look alike, they don’t overlap when you layer them.
Usually these mirror image versions have very similar properties because they share the same elements and links. But the way they are arranged in space can drastically change the effects they have on the body. Just as you couldn’t put a left-handed glove on your right hand, a left-handed version of a drug couldn’t fit a target in the body designed to fit a right-handed molecule.
Chiral molecules exist in two versions, or isomers, defined by their optical activity. This means that if you shine polarized light on a chiral molecule, one will spin the light to the left (denoted by the prefix L-, or levorotatory) while the other will spin it to the right (denoted by the prefix D, or dextrorotatory).
Amino acids, building blocks of proteins, are chiral molecules. Living organisms mainly make proteins from L-configuration amino acids. D-configuration, however, has many other functions in nature. Bacteria, for example, use D-configuration amino acids to make their cell walls. Mammals use D-configuration amino acids as messengers in their nervous and endocrine systems.
The amino acid tyrosine is an important exception to the L configuration rule. Unlike other amino acids, the L and D configurations of tyrosine can be activated for protein synthesis by an enzyme called tyrosyl-tRNA synthetase (TyrRS ).
The presence of D-tyrosine can make it difficult for cells to synthesize proteins that only use L-tyrosine. However, the cells have evolved enzymes that can distinguish between the two versions and ensure that only L-tyrosine is used. When tyrosine-consuming enzymes are absent, the resulting increased levels of tyrosine in the body can have toxic effects, including damage to the nervous system.
Recently published work from my lab suggests a potential reason why too much tyrosine may be neurotoxic. When we added increasing amounts of L-tyrosine to rat brain cells in a petri dish, we found it decreased levels of TyrRS, the enzyme that activates tyrosine to make proteins without causing brain damage. body. Surprisingly, adding D-tyrosine not only caused TyrRS levels to drop, but also killed neurons.
When we looked at the brains of Alzheimer’s patients who had increased levels of tyrosine, we also found that levels of the TyrRS enzymes were depleted. Our hypothesis is that as tyrosine levels in the brain rise, levels of TyrRS enzymes drop and cause adverse effects in the brains of people with Alzheimer’s disease. These findings indicate the potentially important role that TyrRS may play in the synthesis of proteins essential for cognition and memory.
Raisins, peanuts and Alzheimer’s
These findings have implications for studies of resveratrol, a compound found in red wine that researchers have examined for potential health benefits. While some clinical trials have shown that resveratrol can improve cognitive function in people with Alzheimer’s disease, others have found that it has the opposite effect and makes the disease worse. Why resveratrol can have such varied effects has remained a scientific enigma.
Resveratrol comes in two forms, cis-resveratrol and trans-resveratrol. The prefixes “cis-” and “trans-“, just like L- and D-, describe how the same atoms of two isomers are arranged differently in space.
My colleagues and I found that because the two forms of resveratrol bind to TyrRS in different ways, they can cause opposite effects in neurons. While cis-resveratrol was able to increase TyrRS levels in rat neurons in a Petri dish, high concentrations of trans-resveratrol depleted TyrRS and caused neural damage. However, low levels of trans-resveratrol can convert to cis-resveratrol in the body. This result leads to increased levels of TyrRS and its associated benefits.
We hypothesize that many resveratrol clinical trials have failed because none have tested cis-resveratrol alone. We believe this may also explain why trials using high doses of trans-resveratrol saw harmful effects, while trials using low doses of trans-resveratrol that was then converted to cis-resveratrol in the body saw beneficial effects.
Beyond the individual atoms and bonds of molecules, the body also cares about how they are arranged in space. Paying attention to the different forms a drug takes could help lead to more effective treatments.
Sajish Mathew, Assistant Professor of Drug Discovery and Biomedical Sciences, University of South Carolina
This article is republished from The Conversation under a Creative Commons license. Read the original article.